Perineural invasion represents the most common and significant mechanism of prostate cancer spread progression outside the prostate capsule. Specific biological mechanisms are poorly understood. Although it has been proposed for sometime that perineural invasion is a key component of progression, the potential use of perineural invasion markers as prognosticators of disease outcome has not been adequately examined. It is likely that novel markers of perineural invasion may be useful as prognostic tools and mechanisms of perineural invasion may be of therapeutic utility. Our previous studies have focused on the development of an in vitro model system of perineural invasion using human prostate cancer cells and dorsal root ganglion in co-culture. Additionally, we have identified that perineural invasion is associated with inhibition of apoptosis in cancer cells in the perineural space, both in human tissue specimens and in the in vitro model system. Our studies to date indicate that caveolin-1 expression and secretion in the perineural space may be responsible for the antiapoptotic effects. Additionally, NF kappa B, defender against death (DAD) protein and PIM2 have been identified as putative antiapoptotic regulatory molecules in cancer cells in the perineural microenvironment. Accordingly, there is now considerable evidence linking perineural invasion with antiapoptosis of cancer cells and a selective survival advantage in this environment. It is our hypothesis that the interactions between malignant prostate epithelial cells and nerves result in survival advantage through inhibition of apoptosis of the cancer cells in the perineural space and that markers of this process can be used as a prognostic indicator. To address this hypothesis in detail we propose to identify the factors which regulate antiapoptosis in the perineural space, to identify intracellular mechanisms involved in cancer cell enhanced survival, and to develop these factors into a multifaceted prognostic protocol of perineural invasion index to be used with either surgical specimens or with biopsy specimens. These studies will identify key mechanisms and components in perineural invasion and utilize these components in the development of enhanced prognostic procedures. Our long-range interest is to utilize mechanisms identified in this study is to design and test a novel anti-perineural invasion therapeutic approach.